Hollow drug-filled stent and method of forming hollow drug-filled stent

ABSTRACT

A stent is formed from a wire having an outer member, a radiopaque member lining at least a portion of the outer member inner surface, and a lumen defined by the outer member inner surface or the radiopaque member inner surface. A substance is disposed in the lumen to be eluted through at least one opening disposed through the outer member to the lumen. The radiopaque member may be substantially continuous along the length of the wire or disposed only along portions of the wire such as crowns. In a method for making the stent, a composite wire including an outer member, a radiopaque intermediate member, and a core member is shaped into a stent pattern and processed to remove the core member and optionally portions of the radiopaque intermediate member, without damaging the outer member.

FIELD OF THE INVENTION

The present invention relates hollow drug-filled stents and methods offorming hollow-drug-filled stents, and in particular, hollow-drug filledstents with improved radiopacity.

BACKGROUND OF THE INVENTION

Drug-eluting implantable medical devices such as stents have becomepopular in recent times for their ability to perform their primaryfunction (such as structural support) and their ability to medicallytreat the area in which they are implanted.

For example, drug-eluting stents have been used to prevent restenosis incoronary arteries. Drug-eluting stents may administer biologically orpharmacologically active substances such as anti-inflammatory compoundsthat block local invasion/activation of monocytes, thus preventing thesecretion of growth factors that may trigger VSMC proliferation andmigration. Other potentially anti-restenotic compounds includeanti-proliferative agents, such as chemotherapeutics, which includerapamycin and paclitaxel. Other classes of drugs such asanti-thrombotics, anti-oxidants, platelet aggregation inhibitors andcytostatic agents have also been suggested for anti-restenotic use.

Drug-eluting medical devices may be coated with a polymeric materialwhich, in turn, is impregnated with a biologically or pharmacologicallyactive substance or a combination of biologically or pharmacologicallyactive substances. Once the medical device is implanted at a targetlocation, the biologically or pharmacologically active substance isreleased from the polymer for treatment of the local tissues. Thebiologically or pharmacologically active substance is released by aprocess of diffusion through the polymer layer for biostable polymers,and/or as the polymer material degrades for biodegradable polymers.

Controlling the rate of elution of a biologically or pharmacologicallyactive substance from the impregnated polymeric material is generallybased on the properties of the polymer material. However, at theconclusion of the elution process, the remaining polymer material insome instances has been linked to an adverse reaction with the vessel,possibly causing a small but dangerous clot to form. Further, drugimpregnated polymer coatings on exposed surfaces of medical devices mayflake off or otherwise be damaged during delivery, thereby preventingthe biologically or pharmacologically active substance from reaching thetarget site. Still further, drug impregnated polymer coatings arelimited in the quantity of the biologically or pharmacologically activesubstance to be delivered by the amount of a drug that the polymercoating can carry and the size of the medical devices. Controlling therate of elution using polymer coatings is also difficult.

Accordingly, stents with hollow, drug-filled structural members havealso been contemplated. For example, U.S. Pat. No. 6,071,305 to Brown etal. generally discloses a stent formed of an elongated member in aspiral tube configuration. The elongated member includes a groove thatcan be filled with an active agent. Further, U.S. ApplicationPublication No. 2011/0008405 to Birdsall et al. and U.S. ApplicationPublication No. 2011/0070358 to Mauch et al., each of which isincorporated by reference herein in its entirety, describe methods offorming stents with hollow-drug-filled structural members from compositewires. However, preferred structural members for stents, such asnickel-titanium alloys (“nitinol”) and alloys of cobalt, nickel,chromium and molybdenum (“MP35N”, “MP20N”) are relatively radiolucent.Thus, there is a need for a stent with hollow-drug filled structuralmembers with improved radiopacity.

SUMMARY OF INVENTION

Embodiments hereof relate to a stent formed from a wire shaped into astent pattern. The wire includes an outer member having an outer memberouter surface and an outer member inner surface and a radiopaque memberlining at least a portion of the outer member inner surface. A lumen isdefined by the outer member inner surface or the radiopaque member innersurface. A biologically or pharmacologically active substance disposedin the lumen. At least one opening disposed through the outer member tothe lumen or through the outer member and the radiopaque member to thelumen such that the biologically or pharmacologically active substancemay be eluted from the stent. In one embodiment, the stent pattern mayinclude a series of struts connected by crowns, and the radiopaquemember may line the outer member inner surface only in the crowns of thestent. In another embodiment, the radiopaque member is substantiallycontinuous along the length of the stent.

Embodiments hereof also relate to a method of forming such a stent. Acomposite wire including an outer member, a radiopaque intermediatemember, and a core member is shaped into a stent pattern. The compositewire is processed such that the core member is removed without adverselyaffecting the outer member, thereby leaving an outer member, theradiopaque intermediate member lining at least a portion of an innersurface of the outer member, and a lumen defined by a space formerlyoccupied by the core member. The process for removing that core membermay also remove portions of the radiopaque intermediate member. Openingsare formed through at least the outer member such that the openingsextend to the lumen. At least a portion of the lumen is filled with abiologically or pharmacologically active substance. In one embodiment,the composite wire is shaped into a waveform including struts andcrowns, and the process for removing the core member also removesportions of the radiopaque intermediate member from the struts of thewaveform, thereby leaving the radiopaque intermediate member in thecrowns of the waveform. In another embodiment, the process for removingthe core member does not adversely affect the radiopaque intermediatemember, thereby leaving the radiopaque intermediate member substantiallycontinuous along the length of the wire (the radiopaque intermediatemember may be removed at locations of openings, for example, and stillbe substantially continuous).

Embodiments hereof also relate to a stent including a wire formed into astent pattern. The wire includes an outer member, a radiopaque coremember disposed within at least a portion of the outer member, whereinan outer dimension of the radiopaque core member is smaller than aninner dimension of the outer member such that an annular lumen isdefined between an outer surface of the radiopaque core member and aninner surface of the outer member. A biologically or pharmacologicallyactive substance disposed in the annular lumen, and at least one openingdisposed through the outer member. In one embodiment, a plurality ofradiopaque core members are disposed within portions of the outer memberand are separated by lumens defined by the inner surface of the outermember. The lumens and annular lumens between an outer surface of theradiopaque core member and the inner surface of the outer member are influid communication with each other.

Embodiments hereof also relate to a method of making such a stent. Acomposite wire is shaped into a stent pattern. The composite wireincludes an outer member, an intermediate member, and a radiopaque coremember. The composite wire is processed such that the core member isremoved from portions of the composite wire without adversely affectingthe outer member. The composite wire is also processed such that theintermediate member is removed, thereby leaving the outer member andlumens defined by an outer member inner surface in portions where theradiopaque core member is removed, and the outer member, radiopaque coremember, and annular lumens defined between a radiopaque core memberouter surface and the outer member in surface in areas where theradiopaque core member is not removed. A biologically orpharmacologically active substance is deposited in the lumens andannular lumens. Openings are provided through the outer member such thatthe biologically or pharmacologically active substance can be elutedfrom the lumens. The steps of processing the composite wire to removeportions of the radiopaque core member and processing the composite wireto remove the intermediate member can be separate steps, or can becombined where the process removes the intermediate member at a fasterrate than the radiopaque core member.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following description of the invention as illustratedin the accompanying drawings. The accompanying drawings, which areincorporated herein and form a part of the specification, further serveto explain the principles of the invention and to enable a personskilled in the pertinent art to make and use the invention. The drawingsare not to scale.

FIG. 1 is a schematic illustration of an exemplary stent in accordancewith an embodiment hereof.

FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. 1.

FIG. 3 is flow chart illustrating an embodiment of a method of forming ahollow wire stent including a radiopaque intermediate member disposed onan inner surface of a hollow outer member and a biologically orpharmacologically active substance disposed within a lumen of the hollowwire.

FIG. 4 is a schematic illustration of a composite wire including anouter member, an intermediate member, and a core member.

FIGS. 5-7 are cross-sectional views of the composite wire of FIG. 4 atvarious stages of the method of FIG. 3.

FIG. 8 is a schematic illustration of an exemplary stent in accordancewith an embodiment hereof.

FIG. 9 is a cross-sectional view taken along line 9-9 of FIG. 8.

FIG. 10 is a cross-sectional view taken along line 10-10 of FIG. 8.

FIG. 11 is a longitudinal cross-section of a portion of the stent ofFIG. 8.

FIG. 12 is flow chart illustrating an embodiment of a method of forminga hollow wire stent including a radiopaque intermediate member disposedon an inner surface of a hollow outer member at the crowns of the stentand a biologically or pharmacologically active substance disposed withina lumen of the hollow wire.

FIGS. 13-18 are cross-sectional and longitudinal cross-sectional viewsof the composite wire at various stages of the method of FIG. 12.

FIG. 19 is a schematic illustration of an exemplary stent in accordancewith an embodiment hereof.

FIG. 20 is a cross-sectional view taken along line 20-20 of FIG. 19.

FIG. 21 is a cross-sectional view taken along line 21-21 of FIG. 19.

FIG. 22 is a partial longitudinal cross-section of a portion of thestent of FIG. 19.

FIG. 23 is flow chart illustrating an embodiment of a method of forminga hollow wire stent including a radiopaque core member disposed at thecrowns of the stent with a lumen between the core member and the outermember and a biologically or pharmacologically active substance disposedwithin the lumen of the outer member at the struts and in the lumenbetween the core member and the outer member at the crowns.

FIGS. 24-33 are cross-sectional and partial longitudinal cross-sectionalviews of the composite wire at various stages of the method of FIG. 23.

DETAILED DESCRIPTION OF THE INVENTION

Specific embodiments of the present invention are now described withreference to the figures, where like reference numbers indicateidentical or functionally similar elements.

An embodiment of a stent 100 disclosed herein is shown in FIGS. 1-2. Inparticular, stent 100 is formed from a hollow wire 102, wherein thehollow wire 102 is formed of a hollow outer member 122 and a hollowintermediate member 124 that lines the inner surface 121 of outer member122, with a lumen 103 formed within the outer and intermediate members122, 124. The term “wire” as used herein means an elongated element orfilament or group of elongated elements or filaments and is not limitedto a particular cross-sectional shape or material, unless so specified.In the embodiment shown in FIG. 1, hollow wire 102 is formed into aseries of generally sinusoidal waveforms including generally straightsegments or struts 106 joined by bent segments or crowns 108 and thewaveform is helically wound to form a generally tubular stent 100. Inthe embodiment shown in FIG. 1, selected crowns 108 of longitudinallyadjacent sinusoids may be joined by, for example, fusion points 110. Theinvention hereof is not limited to the pattern shown in FIG. 1. Wire 102of stent 100 can be formed into any pattern suitable for use as a stent.For example, and not by way of limitation, wire 102 of stent 100 can beformed into patterns disclosed in U.S. Pat. No. 4,800,882 to Gianturco,U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor,U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle, andU.S. Pat. No. 5,019,090 to Pinchuk, each of which is incorporated byreference herein in its entirety. Further, instead of a single length ofwire formed into a stent pattern, a plurality of wires may be formedinto a two-dimensional waveform and wrapped into individual cylindricalelements. The cylindrical elements may then be aligned along a commonlongitudinal axis and joined to form the stent.

As shown in FIG. 2, hollow wire 102 of stent 100 includes a hollowradiopaque intermediate member 124 that has an outer diameter that isapproximately equal to the inner diameter of hollow outer member 122. By“approximately equal” it is meant that the outer surface of intermediatemember 124 is in contact with the inner surface of outer member 122.Lumen 103 is formed from the hollow portion of radiopaque intermediatemember 124 and the hollow portion of outer member 122 that is notoccupied by radiopaque intermediate member 124. Radiopaque intermediatemember 124 allows stent 100 to be visible under X-ray or fluoroscopicimaging equipment when outer member 122, described below, is made of amaterial that has a radiopacity such that it has poor visibility or isdifficult to visualize under X-ray or fluoroscopic imaging equipment.Thus, radiopaque intermediate member 124 is more radiopaque than outermember 122. The term “radiopaque” refers to the ability of a substanceto absorb X-rays. Few substances will transmit 100% of X-rays and fewsubstances will absorb 100% of X-rays. For the purposes of thisdisclosure, radiopaque will refer to those substances or materials whichhave suitable visibility for stent procedures when being imaged by anX-ray imaging device such as but not limited to a fluoroscope.

Lumen 103 allows for a biologically or pharmacologically activesubstance 112 to be deposited therewithin. Although hollow wire 102 isshown as generally having a circular cross-section, hollow wire 102 maybe generally elliptical or rectangular in cross-section. Hollow wire 102further includes cuts or openings 104 dispersed along its length toprovide access to lumen 103 to permit biologically or pharmacologicallyactive substance 112 to be released from lumen 103. Openings 104 may bedisposed only on struts 106 of stent 100, only on crowns 108 of stent100, or both struts 106 and crowns 108. Openings 104 may be sized andshaped as desired to control the elution rate of biologically orpharmacologically active substance 112 from stent 100. Larger sizedopenings 104 generally permit a faster elution rate and smaller sizedopenings 104 generally provide a slower elution rate. Further, the sizeand/or quantity of openings 104 may be varied along stent 100 in orderto vary the quantity and/or rate of biologically or pharmacologicallyactive substance 112 being eluted from stent 100 at different portionsof stent 100. Openings 104 may be, for example and not by way oflimitation, 5-30 μm in diameter. Openings 104 may be provided on anoutwardly facing or abluminal surface 116 of stent 100, as shown in FIG.1, or on the inwardly facing or luminal surface 118 of stent 100, or maybe provided anywhere along the circumference of wire 102. Openings 104may have a constant diameter through the depth or have a tapered orconical shape.

Ends 114 of wire 102 may be closed. Ends 114 may be closed by crimpingexcess material of wire 102 to close lumen 103. Ends 114 may also beclosed by not removing intermediate member 124 and core member 126,described in more detail below, from the ends 114. Closing ends 114prevents biologically or pharmacologically active substance 112 fromprematurely releasing from ends 114. However, closing ends 114 is notrequired as substance 112 may be dried, provided within a polymermatrix, enclosed within a liner (not shown), or otherwise protected frompremature release from ends 114. Further, ends 114 may be welded,crimped or otherwise connected to other portions of wire 102 such thatthe ends 114 are not free ends. Ends 114 may alternatively be providedas free ends.

FIGS. 3-7 show a method for forming a hollow wire stent in accordancewith an embodiment hereof. As shown in FIG. 3, step 200 is to utilize acomposite wire 120 having an outer member 122, a radiopaque intermediatemember 124, and a core member 126, as shown schematically in FIG. 4.Outer member 122 and radiopaque intermediate member 124 become hollowwire 102 of stent 100 described above after processing described below.Composite wire 120 may be formed by any method known in the art, forexample and not by way of limitation, a co-drawing process, extrusion,cladding, or any other suitable method. Composite wire 120 may be formedby methods of forming composite wires known to those skilled in the art.Examples of composite wires and methods of forming composite wires canbe found in U.S. Pat. No. 5,630,840 to Mayer, U.S. Pat. No. 6,248,190 toStinson, U.S. Pat. No. 6,497,709 to Heath, and U.S. Pat. No. 7,101,392to Heath, each of which is incorporated by reference herein in itsentirety.

Outer member 122 may be any material that is suitable to be used as astent, provided that it survives the process of removing core member126, as described in more detail below. For example and not by way oflimitation, outer member 122 may be a stainless steel, cobalt-chromiumalloys, nickel titanium alloys such as Nitinol, magnesium, orcombinations thereof. The term “cobalt-chromium” alloys as used hereinincludes alloys with cobalt and chromium. Generally, materials such as,but not limited to, cobalt-nickel-chromium alloys (“MP35N” and “MP20N”)and chromium-nickel-tungsten-cobalt alloys (“L605”) andcobalt-chromium-nickel-molybdenum alloys (“ELGILOY”) are the types ofmaterials included in the term “cobalt-chromium alloys” as used herein.The requirements for the material of outer member 122 are that it bebiocompatible, sufficiently resilient to be used as a stent, and that itsurvives the process for eliminating core member 126, as discussed inmore detail below.

Intermediate member 124 is a radiopaque material. Further, intermediatemember 124 is a material that survives the process of eliminating coremember 126, as described in detail below. Accordingly, intermediatemember 124 is more radiopaque that outer member 122 and survives theprocess of eliminating core member 126. Thus, selection of intermediatemember 124 depends on the material of core member 126 and the processselected for removing core member 126. Core member 126 is a sacrificialmaterial that is removed without damaging intermediate member 124 orouter member 122. In a non-limiting example, outer member 122 is made ofMP35N, intermediate member 124 is made of platinum-iridium alloy such asPt10Ir or Pt20Ir, and core member 126 is made of tantalum, and theprocess to remove core member 126 is exposing core member 126 to xenondifluoride gas (XeF₂) gas at low pressure (1-6 Torr) and relatively hightemperature (approximately 150° C.). Pt10Ir is a platinum-iridium alloycontaining about 90% platinum by weight and about 10% iridium by weight.Similarly, Pt20Ir is a platinum-iridium alloy containing about 80%platinum by weight and about 20% iridium by weight. Other examples ofmaterial combinations of outer member 122, intermediate member 124, coremember 126, and the removal method are provided below in chart form.

A cross-section of composite wire 120 is shown in FIG. 5. Outer member122 may have an outer diameter D1 in the range of 0.0017 inch to 0.016inch and wall thickness T in the range of 0.0005 to 0.0025 inch,depending on the application, for example, in what lumen or organ andfor what purpose the stent is to be utilized. Intermediate member 124may have an inner diameter of about 0.0005 to 0.006 inch and a thicknessin the range of about 0.0001 to about 0.0025 inch. Core member 126 mayhave a diameter of about 0.0005 to about 0.006 inch. In one non-limitingexample, core member 126 has a diameter of 0.001 inch, intermediatemember 124 has a wall thickness of 0.0005 inch, and outer member 122 hasa wall thickness of 0.00075 inch, resulting in an outer diameter D1 ofcore wire 120 0.0035 inch. The values listed above are merely examplesand other diameters and thicknesses may be used depending on, forexample, the materials used, the desired stent shape, and the purpose orlocation of the stent. Further, although the dimensions listed aredescribed as diameters, other shapes of wire may be utilized and thevalues listed above can be converted to outer and inner dimensions.

Referring back to FIG. 3, step 210 is to shape the composite wire 120into the stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 1 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step210 should be done prior to removing core member 126, as explained inmore detail below. However, the step of shaping the composite member 120into the stent pattern does not have to include shaping composite member120 into the final stent pattern. For example, the step 210 of shapingthe composite member 120 into a stent pattern may include only formingthe struts 106 and crowns 108 in composite wire 120. Shaping compositewire 120 into the stent pattern while core member 126 and intermediatemember 124 are disposed within outer member 122 helps prevent kinking orother deformations from occurring in outer member 122. Shaping thecomposite wire 120 into the stent pattern shown in FIG. 1 generallyincludes the steps of forming composite wire 120 into a two dimensionalwaveform pattern followed by wrapping the pattern around a mandrel, asknown to those skilled in the art. The end result is a helical stentpattern formed onto a mandrel. Selected crowns 108 of the helicalpattern may then be fused together and the stent may be removed from themandrel. Step 210 of shaping composite wire 120 into the stent patterncan be performed with techniques known to those skilled in the art. Forexample, and not by way of limitation, forming the composite wire 120into a two dimensional waveform can be achieved using techniquesdescribed in U.S. Application Publication Nos. 2010/0269950 to Hoff etal. and 2011/0070358 to Mauch et al., and co-pending U.S. applicationSer. Nos. 13/191,134 and 13/190,775, filed Jul. 26, 2011, each of whichis incorporated in its entirety by reference herein. Other techniquesknown to those skilled in the art could also be used.

Step 220 shown in FIG. 3 is to provide openings 104 through outer member122 and intermediate member 124. Openings 104 may be laser cut, drilled,etched, or otherwise provided through outer member 122 and intermediatemember 124. Step 220 need not be performed after step 210, nor beforestep 230, although it is preferred to be before step 230, as explainedin more detail below. If step 220 is performed after step 210, across-section of composite wire 120 will include outer member 122,intermediate member 124, core member 126, and an opening 104, as shownin FIG. 6.

Step 230 is to remove core member 126 from lumen 103 of outer member 122and intermediate member 124 without adversely affecting outer member 122or intermediate member 124, such as by chemical etching. Step 230 can beperformed by any suitable process for removing core member 126 whilepreserving outer member 122 and intermediate member 124. In particular,exposing composite wire 120 formed from a outer member 122 of MP35N, anintermediate member 124 of a platinum-iridium alloy (such as PT10Ir orPt20Ir), and a core member 126 of tantalum to xenon difluoride (XeF₂)gas at low pressure (1-6 Torr) and relatively high temperature(approximately 150° C.) causes the xenon difluoride (XeF₂) gas to reactwith the tantalum core member 126 to form TaF₅ and Xe gases, which canbe exhausted from lumen 103. Xenon difluoride (XeF₂) gas reactssimilarly with a core member 126 made from tungsten, molybdenum,niobium, rhenium, carbon, germanium, and silicon. However, xenondifluoride (XeF₂) gas does not react with an outer member 102 formed ofMP35N or an intermediate member 124 formed of platinum-iridium alloyssuch as Pt20Ir and Pt10Ir described above. Accordingly, after step 230is completed, outer member 122 and intermediate member 124 remain, andcore member 126 has been removed, leaving the cross-sectional structureshown in FIG. 7. As noted above, openings 104 do not need to be formedprior to the step of removing core member 126 as long as there is a wayto expose core member 126 to the etchant. For example, ends 114 of thewire may be open or temporary ports may for formed through outer member122 and intermediate member 124 to expose core member 126 to theetchant.

Although a particular embodiment of an outer member 122 made from MP35N,an intermediate member 124 made from a platinum iridium alloy, a coremember 126 made from tantalum, and a xenon difluoride etchant has beendescribed, those skilled in the art would recognize other combinationsof materials and etchants that could be utilized. For example, and notby way of limitation, the combination of materials and etchantsdescribed in the chart below may be utilized.

Outer Intermediate Etchant Member Member Core Member Xenon-Cobalt-chromium Pt20Ir, Tantalum, tungsten, difluoride alloys (MP35N,Pt10Ir molybdenum, MP20N, L605, niobium, ELGILOY) rhenium, carbon,germanium, silicon, Ta—2.5W Nitric Cobalt-chromium Tantalum, CopperAcid, alloys (MP35N, Ta—2.5W sulfuric MP20N, L605, acid ELGILOY)Nitinol, Titanium, Titanium alloys Nitric Cobalt-chromium Tantalum,Silver Acid alloys (MP35N, Ta—2.5W MP20N, L605, ELGILOY) Nitinol,Titanium, Titanium alloys Water, Cobalt-chromium Pt20Ir, Zinc, saltwater alloys(MP35N, Pt10Ir, Magnesium MP20N, L605, Tantalum, ELGILOY),Ta—2.5W stainless steel, Nitinol, Titanium, Titanium alloys HeatCobalt-chromium Pt20Ir, Zinc, (separation alloys(MP35N, Pt10Ir,Magnesium via melt or MP20N, L605, Tantalum, sublimation) ELGILOY),Ta—2.5W stainless steel, Nitinol, Titanium, Titanium alloys XenonCobalt-chromium Pt20Ir, Titanium, difluoride alloys(MP35N, Pt10IrTitanium Dilute HF MP20N, L605, alloys ELGILOYFurther, other materials and methods for removing core members may beused, as described, for example, in U.S. Application Publication no.2011/0008405 to Birdsall et al. and U.S. Application Publication No.2011/0070358 to Mauch et al., each of which is incorporated by referenceherein in its entirety.

After core member 126 has been removed, biologically orpharmacologically active substance 112 may be injected into lumen 103 ofouter member 122 and intermediate member 124, as shown in step 240 ofFIG. 3. This produces a hollow wire 102 with outer member 122,radiopaque intermediate member 124 lining an inside surface 121 of outermember 122, biologically or pharmacologically active substance 112filling lumen 103, and openings 104 through which biologically orpharmacologically active substance 112 may be eluted, as shown in FIG.2. Filling lumen 103 with a biologically or pharmacologically activesubstance may be accomplished by any means known to those skilled in theart. For example, and not by way of limitation, methods for fillinglumens of hollow wires described in U.S. Application Publication No.2011/0070357 to Mitchell et al., which is incorporated by referenceherein in its entirety; and co-pending U.S. application Ser. Nos.12/884,362; 12/884,451; 12/884,501; 12/884,578; 12/884,596 each filed onSep. 17, 2010, and each of which is incorporated by reference herein inits entirety.

The biologically or pharmacologically active substance 112 may include,but is not limited to, the substances listed in paragraph [0080] of thisspecification.

FIGS. 8-18 show an embodiment of a stent 300 and a method of makingstent 300. In particular, stent 300 is formed from a hollow wire 302,wherein the hollow wire 302 is formed generally a hollow outer memberwith a lumen formed within the outer member. The term “wire” as usedherein means an elongated element or filament or group of elongatedelements or filaments and is not limited to a particular cross-sectionalshape or material, unless so specified.

In the embodiment shown in FIG. 8, hollow wire 302 is formed into aseries of generally sinusoidal waveforms including generally straightsegments or struts 306 joined by bent segments or crowns 308 and thewaveform is helically wound to form a generally tubular stent 300. Inthe embodiment shown in FIG. 8, selected crowns 308 of longitudinallyadjacent sinusoids may be joined by, for example, fusion points 310. Theinvention hereof is not limited to the pattern shown in FIG. 8. Wire 302of stent 300 can be formed into any pattern suitable for use as a stent.For example, and not by way of limitation, wire 302 of stent 300 can beformed into patterns disclosed in U.S. Pat. No. 4,800,882 to Gianturco,U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor,U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle, andU.S. Pat. No. 5,019,090 to Pinchuk, each of which is incorporated byreference herein in its entirety. Further, instead of a single length ofwire formed into a stent pattern, a plurality of wires may be formedinto a two-dimensional waveform and wrapped into individual cylindricalelements. The cylindrical elements may then be aligned along a commonlongitudinal axis and joined to form the stent.

As shown in FIGS. 9-11, hollow wire 302 of stent 300 includes differentconfigurations for the struts 306 and the crowns 308. In particular,FIG. 9 shows a cross-section of wire 302 at struts 306. As can be seenin FIG. 9, wire 302 at struts 306 is formed from an outer member 322with a lumen 303 filled with a biologically or pharmacologically activesubstance 312. Similarly, as shown in FIG. 10, wire 302 at crowns 308 isformed of a hollow outer member 322, a hollow radiopaque intermediatemember 324 lining the inside surface 321 of outer member 322, and lumen303 filled with biologically or pharmacologically active substance 312.FIG. 11 shows a longitudinal cross-section showing a portion of stent300 including a strut 306, a crown 308, and a second strut 306. As shownin FIG. 11, radiopaque intermediate member 324 lines an inner surface ofouter member 322 in the region of the crowns 308. The length ofradiopaque intermediate member 324 may be varied such that radiopaqueintermediate member 324 extends along the inner surface of outer member322 for the entire crown 308, a portion of crown 308, or all of crown308 and a portion of struts 306, as described in more detail below.Radiopaque intermediate member 324 should extend along crown 308 for atleast a sufficient length such the radiopaque intermediate member isvisible under fluoroscopic equipment. Every crown 308 of stent 300 mayinclude radiopaque intermediate member 324 or only some crowns 308 mayinclude radiopaque intermediate member 324. Some options of how toselect whether or not some crowns 308 include or do not includeradiopaque intermediate member will be described below when describingthe method of forming stent 300. Hollow radiopaque intermediate member324 has an outer diameter that is approximately equal to the innerdiameter of hollow outer member 322. By “approximately equal” it ismeant that the outer surface of intermediate member 324 is in contactwith the inner surface 321 of outer member 322. Radiopaque intermediatemember 324 allows crowns 308 of stent 300 to be visible under X-ray orfluoroscopic imaging equipment when outer member 322, described below,is made of a material that has a radiopacity such that it has poorvisibility or is difficult to visualize under X-ray or fluoroscopicimaging equipment. Thus, radiopaque intermediate member 324 is moreradiopaque than outer member 322. The term “radiopaque” refers to theability of a substance to absorb X-rays. Few substances will transmit100% of X-rays and few substances will absorb 100% of X-rays. For thepurposes of this disclosure, radiopaque will refer to those substancesor materials which have suitable visibility for stent procedures whenbeing imaged by an X-ray imaging device such as but not limited to afluoroscope.

Lumen 303 allows for a biologically or pharmacologically activesubstance 312 to be deposited therewithin. Although hollow wire 302 isshown as generally having a circular cross-section, hollow wire 302 maybe generally elliptical or rectangular in cross-section. Hollow wire 302further includes cuts or openings 304 dispersed along its length toprovide access to lumen 303 to permit biologically or pharmacologicallyactive substance 312 to be released from lumen 303. Openings 304 may bedisposed only on struts 306 of stent 300, only on crowns 308 of stent300, or both struts 306 and crowns 308. Openings 304 may be sized andshaped as desired to control the elution rate of biologically orpharmacologically active substance 312 from stent 300. Larger sizedopenings 304 generally permit a faster elution rate and smaller sizedopenings 304 generally provide a slower elution rate. Further, the sizeand/or quantity of openings 304 may be varied along stent 300 in orderto vary the quantity and/or rate of biologically or pharmacologicallyactive substance 312 being eluted from stent 300 at different portionsof stent 300. Openings 304 may be, for example and not by way oflimitation, 5-30 μm in diameter. Openings 304 may be provided on anoutwardly facing or abluminal surface 316 of stent 100, as shown in FIG.8, or on the inwardly facing or luminal surface 318 of stent 300, or maybe provided anywhere along the circumference of wire 302. Openings 304may have a constant diameter through the depth or have a tapered orconical shape.

Ends 314 of wire 302 may be closed. Ends 314 may be closed by crimpingexcess material of wire 302 to close lumen 303. Ends 314 may also beclosed by not removing intermediate member 324 and core member 326,described in more detail below, from the ends 314. Closing ends 314prevents biologically or pharmacologically active substance 312 fromprematurely releasing from ends 314. However, closing ends 314 is notrequired as substance 312 may be dried, provided within a polymermatrix, enclosed within a liner (not shown), or otherwise protected frompremature release from ends 314. Further, ends 314 may be welded,crimped or otherwise connected to other portions of wire 302 such thatthe ends 314 are not free ends. Ends 314 may alternatively be providedas free ends.

FIGS. 12-18 show a method for forming a hollow wire stent in accordancewith an embodiment hereof. As shown in FIG. 12, step 400 is to utilize acomposite wire 320 having an outer member 322, a radiopaque intermediatemember 324, and a core member 326. Such a composite member 320 may bethe same as composite member 120 shown in FIG. 4, simply replacingreference numerals 120, 122, 124, and 126 with reference numerals 320,322, 324, and 326. Thus, FIG. 4 is not repeated here. A cross-section ofsuch a composite member 320 is shown in FIG. 13 and a longitudinalcross-section of a portion of core wire 320 is shown in FIG. 14.Composite wire 320 may be formed by any method known in the art, forexample and not by way of limitation, a co-drawing process, extrusion,cladding, or any other suitable method. Composite wire 320 may be formedby methods of forming composite wires known to those skilled in the art.Examples of composite wires and methods of forming composite wires canbe found in U.S. Pat. No. 5,630,840 to Mayer, U.S. Pat. No. 6,248,190 toStinson, U.S. Pat. No. 6,497,709 to Heath, and U.S. Pat. No. 7,101,392to Heath, each of which is incorporated by reference herein in itsentirety.

Outer member 322 may be any material that is suitable to be used as astent, provided that it survives the process of removing core member326, as described in more detail below. For example and not by way oflimitation, outer member 322 may be a stainless steel, cobalt-chromiumalloys, nickel-titanium alloys such as Nitinol, magnesium, orcombinations thereof. The term “cobalt-chromium” alloys as used hereinincludes alloys with cobalt and chromium. Generally, materials such as,but not limited to, cobalt-nickel-chromium alloys (“MP35N” and “MP20N”)and chromium-nickel-tungsten-cobalt alloys (“L605”) andcobalt-chromium-nickel-molybdenum alloys (“ELGILOY”) are the types ofmaterials included in the term “cobalt-chromium alloys” as used herein.The requirements for the material of outer member 322 are that it bebiocompatible, sufficiently resilient to be used as a stent, and that itsurvives the process for eliminating core member 326, as discussed inmore detail below.

Intermediate member 324 is a radiopaque material. Further, intermediatemember 324 is a material that is etched more slowly than core member 326when exposed to the selected etchant, as described in more detail below.Accordingly, intermediate member 324 is more radiopaque that outermember 322 and is etched more slowly than core member 326 during theprocess of eliminating core member 326. Thus, selection of the materialfor intermediate member 324 depends on the material of core member 326and the process selected for removing core member 326. Core member 326is a sacrificial material that is removed without damaging outer member322 and without completely removing intermediate member 324. In anon-limiting example, outer member 322 is made of MP35N, intermediatemember 324 is made of tantalum, core member 326 is made of molybdenum,and the etching process to remove core member 326 is exposing coremember 326 to xenon difluoride gas (XeF₂) gas at low pressure (1-6 Torr)and relatively high temperature (approximately 150° C.). Other examplesof material combinations of outer member 322, intermediate member 324,core member 326, and the removal method are provided below in chartform.

A cross-section of composite wire 320 is shown in FIG. 13. Outer member322 may have an outer diameter D1 in the range of 0.0017 inch to 0.016inch and wall thickness T in the range of 0.0005 to 0.0025 inch,depending on the application, for example, in what lumen or organ andfor what purpose the stent is to be utilized. Intermediate member 124may have an inner diameter of about 0.0005 to 0.006 inch and a thicknessof in the range of about 0.0001 to about 0.0025 inch. Core member 126may have a diameter of about 0.0005 to about 0.006 inch. In onenon-limiting example, core member 326 has a diameter of 0.001 inch,intermediate member 324 has a wall thickness of 0.0005 inch, and outermember 322 has a wall thickness of 0.00075 inch, resulting in an outerdiameter D1 of core wire 320 0.0035 inch. The values listed above aremerely examples and other diameters and thicknesses may be useddepending on, for example, the materials used, the desired stent shape,and the purpose or location of the stent. Further, although thedimensions listed are described as diameters, other shapes of wire maybe utilized and the values listed above can be converted to outer andinner dimensions.

Referring back to FIG. 12, step 410 is to shape the composite wire 320into the stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 8 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step410 should be done prior to removing core member 326, as explained inmore detail below. However, the step of shaping the composite member 320into the stent pattern does not have to include shaping composite member320 into the final stent pattern. For example, and not by way oflimitation, the step 410 of shaping the composite member 320 into astent pattern may include only forming a waveform of struts 306 andcrowns 308 in composite wire 320, with the step of helically wrappingthe waveform into the final stent pattern occurring after the coremember 326 has been removed. Shaping composite wire 320 into the stentpattern while core member 326 and intermediate member 324 are disposedwithin outer member 322 helps prevent kinking or other deformations fromoccurring in outer member 322 or intermediate member 324. Shaping thecomposite wire 320 into the stent pattern shown in FIG. 8 generallyincludes the steps of forming composite wire 320 into a two dimensionalwaveform pattern followed by wrapping the pattern around a mandrel, asknown to those skilled in the art. The end result is a helical stentpattern formed onto a mandrel. Selected crowns 308 of the helicalpattern may then be fused together and the stent may be removed from themandrel. Step 410 of shaping composite wire 320 into the stent patterncan be performed with techniques known to those skilled in the art. Forexample, and not by way of limitation, forming the composite wire 320into a two dimensional waveform can be achieved using techniquesdescribed in U.S. Application Publication Nos. 2010/0269950 to Hoff etal. and 2011/0070358 to Mauch et al., and co-pending U.S. applicationSer. Nos. 13/191,134 and 13/190,775, filed Jul. 26, 2011, each of whichis incorporated in its entirety by reference herein. Other techniquesknown to those skilled in the art could also be used.

Step 420 shown in FIG. 12 is to provide openings 304 through outermember 322 and intermediate member 324. Openings 304 may be laser cut,drilled, etched, or otherwise provided through outer member 322 andintermediate member 324. Openings 304 may also be drilled partially orcompletely through core member 326 to provide better access to coremember 326 by the etchant if openings 304 are provided prior to the stepof removing core member 326, as described in more detail below. Step 420need not be performed after step 410, nor before step 430, although itis preferred to be before step 430, as explained in more detail below.If step 420 is performed after step 410, a cross-section of compositewire 320 will include outer member 322, intermediate member 324, coremember 326, and an opening 304, as shown in FIG. 15. Further, alongitudinal cross-section of core wire 320 with opening 304 is shown inFIG. 16.

Step 430 is to remove core member 326 and portions of intermediatemember 324 from within outer member 322 without adversely affectingouter member 322, such as by chemical etching. Step 430 can be performedby any suitable process for removing core member 326 and removingportions of intermediate member 324, while preserving portions ofintermediate member 324 and preserving outer member 322. In particular,in the example provided where radiopaque intermediate member 324 remainsin the crowns 308 of stent 300, openings 304 may be provided throughouter member 322 and intermediate member 324. In such an embodiment, theopenings 304 may be provided only in the portions of composite wire 320which will become the struts 306. The composite wire 320 is then exposedto an etchant (illustrated schematically by arrows 340 in FIG. 17) thatremoves core member 326 at a faster rate than the etchant removesintermediate member 324, as also illustrated schematically in FIG. 17.Core wire 320 is exposed to the etchant for sufficient time tocompletely eliminate core member 326 from struts 306 and crowns 308,although core member 326 may remain at ends 314, as described above.Because intermediate member 324 is removed at a slower rate than coremember 326, intermediate member 324 is not removed from areas remotefrom the exposure point, openings 304 in this example, because theetchant does not have sufficient exposure time to etch these areas ofintermediate member 324. In particular, exposing composite wire 320formed from a outer member 322 of MP35N, an intermediate member 324 oftantalum, and a core member 326 of molybdenum to xenon difluoride (XeF₂)gas at low pressure (1-6 Torr) and relatively high temperature(approximately 150° C.) causes the xenon difluoride (XeF₂) to react withthe molybdenum core member 326 at a faster rate than the tantalumintermediate member 324. By locating the openings 304 at mid-points ofstruts 306 and timing the exposure properly, core member 326 may beremoved from the struts 306 and crowns 308, and intermediate member 324may be removed from the struts 306, but not the crowns 308. If it isdesired that the biologically or pharmacologically active substance 312be eluted from the crowns 308 as well as the struts 306, openings 304can be added to crowns 308 after removal of core member 326. Further, byvarying the thickness of the different layers, exposure conditions, andother variables known to those skilled in the art, the amount andlocation of intermediate member 324 that remains can be controlled. Ifit is desired that only some of the crowns 308 include radiopaqueintermediate member 324 and other crowns 308 do not include radiopaqueintermediate member, openings 304 can be provided at the crowns 308where it is desired that the intermediate member 324 be removed prior toexposure to the etchant. Thus, during removal of the core member 326,intermediate member 324 will also be removed. Intermediate member 324may be maintained, for example and not by way of limitation, in everyother crown, in crowns of every other winding, in crowns only atopposite ends of the stent, or other combinations desired by those ofordinary skill in the art.

Although a particular embodiment of an outer member 322 made from MP35N,an intermediate member 324 made from tantalum, a core member 326 madefrom molybdenum, and a xenon difluoride etchant has been described,those skilled in the art would recognize other combinations of materialsand etchants that could be utilized. For example, and not by way oflimitation, the combination of materials and etchants described in thechart below may be utilized.

Outer Intermediate Etchant Member Member Core Member Xenon- MP35Ntantalum rhenium, molybdenum, difluoride tungsten, and alloys thereof.Further, other materials and methods for removing core members may beused, as described, for example, in U.S. Application Publication no.2011/0008405 to Birdsall et al. and U.S. Application Publication No.2011/0070358 to Mauch et al., each of which is incorporated by referenceherein in its entirety.

Accordingly, after step 430 is completed, outer member 322 remains,intermediate member 324 has been removed from struts 306 but remains atcrowns 308, core member 326 has been removed, and lumen 303 is formed inthe interior of outer member 322 and intermediate member 324 where coremember 326 and intermediate member 324 have been removed. This structureshown in partial longitudinal cross-section in FIG. 18. As noted above,openings 304 do not need to be formed prior to the step of removing coremember 326 and partially removing intermediate member 324 as long asthere is a way to expose core member 326 and intermediate member 324 tothe etchant. For example, and not by way of limitation, temporary portsmay for formed through outer member 322 and intermediate member 324 toexpose core member 326 and intermediate member 324 to the etchant.

After core member 326 has been removed and intermediate member 324 hasbeen partially removed, biologically or pharmacologically activesubstance 312 may be injected into lumen 303, as shown in step 440 ofFIG. 12. This produces a hollow wire 302 with outer member 322,radiopaque intermediate member 324 lining an inside surface of outermember 322 at the crowns 308, biologically or pharmacologically activesubstance 312 filling lumen 303, and openings 304 through whichbiologically or pharmacologically active substance 312 may be eluted, asshown in FIGS. 9-11. Filling lumen 303 with a biologically orpharmacologically active substance may be accomplished by any meansknown to those skilled in the art. For example, and not by way oflimitation, methods for filling lumens of hollow wires described in U.S.Application Publication No. 2011/0070357 to Mitchell et al., which isincorporated by reference herein in its entirety; and co-pending U.S.application Ser. Nos. 12/884,362; 12/884,451; 12/884,501; 12/884,578;12/884,596 each filed on Sep. 17, 2010, and each of which isincorporated by reference herein in its entirety.

The biologically or pharmacologically active substance 312 may include,but is not limited to, the substances listed in paragraph [0080] of thisspecification.

FIGS. 19-33 show an embodiment of a stent 500 and a method of makingstent 500. In particular, stent 500 is formed from a hollow wire 502,wherein the hollow wire 502 is formed generally a hollow outer memberwith a lumen formed within the outer member. The term “wire” as usedherein means an elongated element or filament or group of elongatedelements or filaments and is not limited to a particular cross-sectionalshape or material, unless so specified.

In the embodiment shown in FIG. 19, hollow wire 502 is formed into aseries of generally sinusoidal waveforms including generally straightsegments or struts 506 joined by bent segments or crowns 508 and thewaveform is helically wound to form a generally tubular stent 500. Inthe embodiment shown in FIG. 19, selected crowns 508 of longitudinallyadjacent sinusoids may be joined by, for example, fusion points 510. Theinvention hereof is not limited to the pattern shown in FIG. 19. Wire502 of stent 500 can be formed into any pattern suitable for use as astent. For example, and not by way of limitation, wire 502 of stent 500can be formed into patterns disclosed in U.S. Pat. No. 4,800,882 toGianturco, U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 toWiktor, U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 toBoyle, and U.S. Pat. No. 5,019,090 to Pinchuk, each of which isincorporated by reference herein in its entirety. Further, instead of asingle length of wire formed into a stent pattern, a plurality of wiresmay be formed into a two-dimensional waveform and wrapped intoindividual cylindrical elements. The cylindrical elements may then bealigned along a common longitudinal axis and joined to form the stent.

As shown in FIGS. 20-22, hollow wire 502 of stent 500 includes differentconfigurations for the struts 506 and the crowns 508. In particular,FIG. 20 shows a cross-section of wire 502 at struts 506. As can be seenin FIG. 20, wire 302 at struts 506 is formed from an outer member 522with a lumen 503 filled with a biologically or pharmacologically activesubstance 512. Similarly, as shown in FIG. 21, wire 502 at crowns 508 isformed of a hollow outer member 522 having an inner diameter or innerdimension defined by an inner surface 521 of the outer member 522, aradiopaque core member 526 having an outer diameter or outer dimensionsmaller than the inner diameter/dimension of the outer member, and anannular lumen 503′ disposed between an outer surface of radiopaque coremember 526 and an inner surface of outer member 522. Lumen 503′ is alsofilled with biologically or pharmacologically active substance 512.Lumens 503, 503′ are in fluid communication with each other such thatthere is a continuous lumen from strut to adjacent crown to adjacentstrut, as shown in the longitudinal cross-section of a portion of stent500 shown in FIG. 22. FIG. 22 shows a longitudinal cross-section showinga portion of stent 500 including a strut 506, a crown 508, and a secondstrut 506′, wherein a first end of crown 508 is attached to an end ofstrut 506 and a second end of crown 508 is attached to an end secondstrut 506′. In the embodiment shown, the attachment described is not anattachment of separate parts because wire 502 is continuous. However,stent 500 is not limited to a continuous wire stent. For example, andnot by way of limitation, wires could be placed end to end, attachedtogether, and then formed into stent 500 as described below. As shown inFIG. 22, radiopaque core member 526 is disposed within the interior ofouter member 522 in the region of the crowns 508. The length ofradiopaque core member 526 may be varied such that radiopaque coremember 526 extends within outer member 522 for the entire crown 508, aportion of crown 508, or all of crown 508 and a portion of struts 506adjoining crown 508, as described in more detail below. Radiopaque coremember 526 should extend along crown 508 for at least a sufficientlength such the radiopaque core member 526 is visible under fluoroscopicequipment. Every crown 508 of stent 500 may include radiopaque coremember 526 or only some crowns 508 may include radiopaque intermediatemember 526. Some options of how to select whether or not some crowns 508include or do not include radiopaque intermediate member will bedescribed below when describing the method of forming stent 500.Radiopaque core member 526 allows crowns 508 of stent 500 to be visibleunder X-ray or fluoroscopic imaging equipment when outer member 522,described below, is made of a material that has a radiopacity such thatit has poor visibility or is difficult to visualize under X-ray orfluoroscopic imaging equipment. Thus, radiopaque core member 526 is moreradiopaque than outer member 522. The term “radiopaque” refers to theability of a substance to absorb X-rays. Few substances will transmit100% of X-rays and few substances will absorb 100% of X-rays. For thepurposes of this disclosure, radiopaque will refer to those substancesor materials which have suitable visibility for stent procedures whenbeing imaged by an X-ray imaging device such as but not limited to afluoroscope.

Lumens 503, 503′ allow for a biologically or pharmacologically activesubstance 512 to be deposited therewithin. Although hollow wire 502 isshown as generally having a circular cross-section, hollow wire 502 maybe generally elliptical or rectangular in cross-section. Hollow wire 502further includes cuts or openings 504 dispersed along its length toprovide access to lumen 503 to permit biologically or pharmacologicallyactive substance 512 to be released from lumen 503, 503′. Openings 504may be disposed only on struts 506 of stent 500, only on crowns 508 ofstent 500, or both struts 506 and crowns 508. Openings 504 may be sizedand shaped as desired to control the elution rate of biologically orpharmacologically active substance 512 from stent 500. Larger sizedopenings 504 generally permit a faster elution rate and smaller sizedopenings 504 generally provide a slower elution rate. Further, the sizeand/or quantity of openings 504 may be varied along stent 500 in orderto vary the quantity and/or rate of biologically or pharmacologicallyactive substance 512 being eluted from stent 500 at different portionsof stent 500. Openings 504 may be, for example and not by way oflimitation, 5-30 μm in diameter. Openings 504 may be provided on anoutwardly facing or abluminal surface 516 of stent 500, as shown in FIG.19, or on the inwardly facing or luminal surface 518 of stent 500, ormay be provided anywhere along the circumference of wire 502. Openings504 may have a constant diameter through the depth or have a tapered orconical shape.

Ends 514 of wire 502 may be closed. Ends 514 may be closed by crimpingexcess material of wire 502 to close lumen 503. Ends 514 may also beclosed by not removing intermediate member 524 and core member 526,described in more detail below, from the ends 514. Closing ends 514prevents biologically or pharmacologically active substance 512 fromprematurely releasing from ends 514. However, closing ends 514 is notrequired as substance 512 may be dried, provided within a polymermatrix, enclosed within a liner (not shown), or otherwise protected frompremature release from ends 514. Further, ends 514 may be welded,crimped or otherwise connected to other portions of wire 502 such thatthe ends 514 are not free ends. Ends 514 may alternatively be providedas free ends.

FIGS. 23-33 show a method for forming a hollow wire stent in accordancewith an embodiment hereof. As shown in FIG. 23, step 600 is to utilize acomposite wire 520 having an outer member 522, an intermediate member524, and a radiopaque core member 526. Such a composite member 520 maybe the same as composite member 120 shown in FIG. 4, simply replacingreference numerals 120, 122, 124, and 126 with reference numerals 520,522, 524, and 526. Thus, FIG. 4 is not repeated here. A cross-section ofsuch a composite member 520 is shown in FIG. 24. Composite wire 520 maybe formed by any method known in the art, for example and not by way oflimitation, a co-drawing process, extrusion, cladding, or any othersuitable method. Composite wire 520 may be formed by methods of formingcomposite wires known to those skilled in the art. Examples of compositewires and methods of forming composite wires can be found in U.S. Pat.No. 5,630,840 to Mayer, U.S. Pat. No. 6,248,190 to Stinson, U.S. Pat.No. 6,497,709 to Heath, and U.S. Pat. No. 7,101,392 to Heath, each ofwhich is incorporated by reference herein in its entirety.

Outer member 522 may be any material that is suitable to be used as astent, provided that it survives the process of removing intermediatemember 524 and portions of core member 526, as described in more detailbelow. For example and not by way of limitation, outer member 522 may bea stainless steel, cobalt-chromium alloys, nickel-titanium alloys suchas Nitinol, magnesium, or combinations thereof. The term“cobalt-chromium” alloys as used herein includes alloys with cobalt andchromium. Generally, materials such as, but not limited to,cobalt-nickel-chromium alloys (“MP35N” and “MP20N”) andchromium-nickel-tungsten-cobalt alloys (“L605”) andcobalt-chromium-nickel-molybdenum alloys (“ELGILOY”) are the types ofmaterials included in the term “cobalt-chromium alloys” as used herein.The requirements for the material of outer member 522 are that it bebiocompatible, sufficiently resilient to be used as a stent, and that itsurvives the process for eliminating intermediate member 524 andportions of core member 526, as discussed in more detail below.

Intermediate member 524 is a sacrificial material that is removed by aprocess that does not affect outer member 522 or core member 526.Intermediate member 524 has an outer diameter that is approximatelyequal to the inner diameter of hollow outer member 522. By“approximately equal” it is meant that the outer surface of intermediatemember 524 is in contact with the inner surface of outer member 522.Core member 526 is a radiopaque material that is partially removedwithout damaging outer member 522. Core member 526 is more radiopaquethan outer member 522. The selection of materials for outer member 522,intermediate member 524, and radiopaque core member 526 depends on theprocesses selected for partially removing the core member 526 andremoving the intermediate member 524, as will be described in moredetail below.

A cross-section of composite wire 520 is shown in FIG. 24. Outer member522 may have an outer diameter D1 in the range of 0.0017 inch to 0.016inch and wall thickness T in the range of 0.0005 to 0.0025 inch,depending on the application, for example, in what lumen or organ andfor what purpose the stent is to be utilized. Intermediate member 124may have an inner diameter of about 0.0005 to 0.006 inch and a thicknessof in the range of about 0.0001 to about 0.0025 inch. Core member 126may have a diameter of about 0.0005 to about 0.006 inch. In onenon-limiting example, core member 526 has a diameter of 0.001 inch,intermediate member 524 has a wall thickness of 0.0005 inch, and outermember 522 has a wall thickness of 0.00075 inch, resulting in an outerdiameter D1 of core wire 520 0.0035 inch. The values listed above aremerely examples and other diameters and thicknesses may be useddepending on, for example, the materials used, the desired stent shape,and the purpose or location of the stent. Further, although thecomposite wire has been shown and described as generally circular anddimensions have been referred to as inner and outer diameters, compositewire need not be circular and the inner and outer diameters may bereferred to as inner and outer dimensions.

Referring back to FIG. 23, step 610 is to shape the composite wire 520into the stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 19 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step610 should be done prior to removing core member 526, as explained inmore detail below. However, the step of shaping the composite member 520into the stent pattern does not have to include shaping composite member520 into the final stent pattern. For example, and not by way oflimitation, the step 610 of shaping the composite member 520 into astent pattern may include only forming a waveform of struts 506 andcrowns 508 in composite wire 520, with the step of helically wrappingthe waveform into the final stent pattern occurring after the coremember 526 has been partially removed. Shaping composite wire 520 intothe stent pattern while core member 526 and intermediate member 524 aredisposed within outer member 522 helps prevent kinking or otherdeformations from occurring in outer member 522. Shaping the compositewire 520 into the stent pattern shown in FIG. 19 generally includes thesteps of forming composite wire 520 into a two dimensional waveformpattern followed by wrapping the pattern around a mandrel, as known tothose skilled in the art. The end result is a helical stent patternformed onto a mandrel. Selected crowns 508 of the helical pattern maythen be fused together and the stent may be removed from the mandrel.Step 610 of shaping composite wire 520 into the stent pattern can beperformed with techniques known to those skilled in the art. Forexample, and not by way of limitation, forming the composite wire 520into a two dimensional waveform can be achieved using techniquesdescribed in U.S. Application Publication Nos. 2010/0269950 to Hoff etal. and 2011/0070358 to Mauch et al., and co-pending U.S. applicationSer. Nos. 13/191,134 and 13/190,775, filed Jul. 26, 2011, each of whichis incorporated in its entirety by reference herein. Other techniquesknown to those skilled in the art could also be used.

Step 620 shown in FIG. 23 is to provide openings 504 through outermember 522 and intermediate member 524. Openings 504 may be laser cut,drilled, etched, or otherwise provided through outer member 522 andintermediate member 524. Openings 504 may also be drilled partially orcompletely through core member 526 to provide better access to coremember 526 by the etchant if openings 504 are provided prior to the stepof partially removing core member 526, as described in more detailbelow. Step 620 need not be performed after step 610, nor before step630, although it is preferred to be before step 630, as explained inmore detail below. Further, openings 504 are preferably formed only inthe strut regions 508 of stent 500 prior to step 630 such that coremember 526 is not removed from crowns 508 during step 630. If step 620is performed after step 610, a cross-section of composite wire 520 atthe locations of openings 504 at struts 506 will include outer member522, intermediate member 524, core member 526, and an opening 504, asshown in FIG. 25. Further, a cross-section after step 620 at crowns 508will include outer member 522, intermediate member 524, and core member526, without openings 504, as shown in FIG. 26.

Step 630 is to partially remove core member 526 from within outer member522 without adversely affecting outer member 522, such as by chemicaletching. Step 630 can be performed by any suitable process for partiallyremoving core member 526 while preserving outer member 522. Inparticular, in an example where outer member 522 is made from MP35N,intermediate member 524 is magnesium, zinc, copper, silver, andradiopaque core member 526 is made from tantalum, core member 526 may bepartially removed by exposing core wire 520 to xenon difluoride (XeF₂)gas at low pressure (1-6 Torr) and relatively high temperature(approximately 150° C.), causing the xenon difluoride (XeF₂) to reactwith the tantalum core member 526 to form TaF₅ and Xe gases, which canbe exhausted from lumen 503. By locating the openings 504 at mid-pointsof struts 506 and timing the exposure properly, core member 526 may beremoved from the struts 506, but not from crowns 508, as explained, forexample, in U.S. patent application Ser. No. 12/884,343 filed Sep. 17,2010. FIG. 27 shows schematically a portion of a strut 506 being exposedto xenon difluoride (XeF₂) gas (shown schematically as arrows 540) toetch away core member 526. Upon completion of step 630, a cross-sectionof core wire 520 at an opening 504 through a strut region 506 of stent500 is shown in FIG. 28, showing outer member 522, intermediate member524, lumen 503, and opening 504. After step 630 a similar cross-sectionshown in FIG. 29 taken through a crown region 508 still includes outermember 522, intermediate member 524, and core member 526. FIG. 30 showsa longitudinal cross-section through a portion of shaped core wire 520including a strut 506, crown 508, and a second strut 506′ after step630. As can be seen in FIG. 30, the strut regions 506 include outermember 522 and intermediate member 524, while the crown region 508includes outer member 522, intermediate member 524, and core member 526.

Referring back to FIG. 23, step 640 is to remove intermediate member 526without damaging outer member 522 or the remaining portion of coremember 526. For example, and not by way of limitation, intermediatemember 524 may be removed by a wet etching process, such as nitric acid.In the example provided above, where outer member 522 is made fromMP35N, intermediate member 524 is made from copper, and core member 526is made from tantalum, a selective wet etch of nitric acid can be usedto remove intermediate member 524. Upon completion of step 640, across-section of core wire 520 at an opening 504 through a strut region506 of stent 500 is shown in FIG. 31, showing that intermediate member524 has been removed, thus leaving outer member 522, lumen 503, andopening 504. After step 640 a similar cross-section shown in FIG. 32taken through a crown region 508 also shows intermediate member 524removed, leaving outer member 522, core member 526, and annular lumen503′ disposed between core member 526 and outer member 522. FIG. 33shows a longitudinal cross-section through a portion of shaped core wire520 including a strut 506, crown 508, and a second strut 506′ after step640. As can be seen in FIG. 33, the strut regions 506, 506′ includeouter member 522 and lumen 503, while the crown region 508 includesouter member 522, core member 526, and annular lumen 503′ disposedbetween an outer surface of core member 526 and an inner surface ofouter member 522. As also can be seen in FIG. 33, lumen 503 and annularlumen 503′ are in fluid communication with each other.

Although a particular embodiment of an outer member 522 made from MP35N,an intermediate member 524 made from copper, a radiopaque core member526 made from tantalum, xenon difluoride as the etchant to partiallyremove radiopaque core member 526, and a wet etch of nitric acid to etchremove intermediate member 524 has been described, those skilled in theart would recognize other combinations of materials and etchants thatcould be utilized. For example, and not by way of limitation, thecombination of materials and etchants described in the chart below maybe utilized.

Intermediate Intermediate Core Member Outer Member Member Member EtchantCore Member Etchant cobalt- Magnesium Hydrochloric Tantalum,xenon-difluoride chromium acid, most tungsten, alloys acids, salt watermolybdenum, (MP35N, solution niobium, MP20N, L605, rhenium, Ta—2.5WELGILOY) Cobalt- Zinc Hydrochloric, chromium Nitric acid alloys (MP35N,MP20N, L605, ELGILOY) Cobalt- Copper, silver Nitric acid chromium alloys(MP35N, MP20N, L605, ELGILOY) Cobalt- Gold Potassium chromium triiodide,allows cyanide (MP35N, solutions MP20N, L605, ELGILOY) cobalt- Tantalum,xenon-difluoride Gold Potassium chromium tungsten, triiodide, cyanidealloys molybdenum, solutions (MP35N, niobium, MP20N, L605, rhenium,carbon, ELGILOY) germanium, silicon, Ta—2.5WFurther, other materials and methods for removing core members may beused, as described, for example, in U.S. Application Publication no.2011/0008405 to Birdsall et al. and U.S. Application Publication No.2011/0070358 to Mauch et al., each of which is incorporated by referenceherein in its entirety.

Accordingly, after step 640 is completed, outer member 522 remains,intermediate member 524 has been removed, and core member has beenremoved from struts 506 but remains at crowns 508, leaving the structureshown in partial longitudinal cross-section in FIG. 33. As noted above,openings 504 do not need to be formed prior to the step of partiallyremoving core member 526 and removing intermediate member 524 as long asthere is a way to expose core member 526 and intermediate member 524 tothe etchants. For example, and not by way of limitation, temporary portsmay be formed through outer member 522 and intermediate member 524 toexpose them to the etchants. Further, although it is explained abovethat in step 630 of partially removing core member 526 openings 504 aredisposed only in strut regions 506, this does not mean that openingscannot be formed in crowns 508. If it is desired that the biologicallyor pharmacologically active substance 512 be eluted from the crowns 508as well as the struts 506, openings 504 can be added to crowns 508 afterpartial removal of core member 526, or openings 504 can be formed priorto partial removal of core member 526 and the openings 504 can be maskedoff during exposure to the etchant so as not to remove core member 526from the crowns 508. Further, although it has been disclosed thatradiopaque core member 526 is removed from strut regions 506 and remainsin crown regions 508, core member 526 does not need to remain at everycrown 508. For example, and not by way of limitation, core member mayremain only in every other crown, in one crown per winding, in allcrowns for every other winding, in crowns at each end or only one end ofthe stent, or other combinations desired by those skilled in the artbased upon the teachings of this disclosure. Some such methods andcombinations are explained in U.S. application Ser. No. 12/884,343 filedSep. 17, 2010, which is incorporated by reference herein in itsentirety.

After core member 526 has been partially removed and intermediate member524 has been removed, biologically or pharmacologically active substance512 may be injected into lumen 503, 503′, as shown in step 650 of FIG.23. This produces a hollow wire 502 with outer member 522, radiopaquecore member 526 at crowns 508, biologically or pharmacologically activesubstance 512 filling lumen 503 in struts 506 and lumen 503′ at crowns508, and openings 504 through which biologically or pharmacologicallyactive substance 512 may be eluted, as shown in FIGS. 20-22. Fillinglumen 503, 503′ with a biologically or pharmacologically activesubstance may be accomplished by any means known to those skilled in theart. For example, and not by way of limitation, methods for fillinglumens of hollow wires described in U.S. Application Publication No.2011/0070357 to Mitchell et al., which is incorporated by referenceherein in its entirety; and co-pending U.S. application Ser. Nos.12/884,362; 12/884,451; 12/884,501; 12/884,578; 12/884,596 each filed onSep. 17, 2010, and each of which is incorporated by reference herein inits entirety.

The biologically or pharmacologically active substance 512 may include,but is not limited to, the substances listed in paragraph [0080] of thisspecification.

Those of ordinary skill in the art would recognize that the methodsdescribed with respect FIGS. 12 and 23 to make the stents shown anddescribed with respect to FIGS. 8-11 and 19-22, respectively, may bereversed/modified such that the method of FIG. 12 can produce the stentof FIGS. 19-22 and the method of FIG. 23 can produce the stent of FIGS.8-11. For example, relying on the method of FIG. 12, the intermediatemember may be selected to etch faster than a radiopaque core member.Thus, when exposed to an etchant, such as xenon difluoride, the exposurecan be timed such that the intermediate member is completely removed andthe radiopaque core member is removed from the struts, but not thecrowns. After filling the lumen with a biologically or pharmacologicallyactive substance, the method results in the stent shown and describedwith respect to FIGS. 19-22. Similarly, the method described withrespect to FIG. 23 can be used to produce the stent described withrespect to FIGS. 8-11. In particular, a dry etch such as xenondifluoride gas can be used to remove the core member, and a wet etch cansubsequently be used to remove radiopaque intermediate member from thestrut regions and not remove radiopaque intermediate member from thecrown regions. After filling the lumen with a biologically orpharmacologically active substance, the method results in the stentshown and described with respect to FIGS. 8-11. Those skilled in the artwould be capable of making the necessary adjustments in the methods,such as but not limited to materials used and timing of the steps, toproduce the desired stent.

The biologically or pharmacologically active substance 112, 312, 512 mayinclude, but are not limited to, biologoicantineoplastic, antimitotic,antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin,antiproliferative, antibiotic, antioxidant, and antiallergic substancesas well as combinations thereof. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., Taxotere® from Aventis S. A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include ABT-578 (asynthetic analog of rapamycin), rapamycin (sirolimus), zotarolimus,everolimus, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril (e.g., Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g., Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.), calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other biologically orpharmacologically active substances or agents that may be used includenitric oxide, alpha-interferon, genetically engineered epithelial cells,and dexamethasone. In other examples, the biologically orpharmacologically active substance is a radioactive isotope forimplantable device usage in radiotherapeutic procedures. Examples ofradioactive isotopes include, but are not limited to, phosphorus (P³²),palladium (Pd¹⁰³), cesium (Cs¹³¹), Iridium (I¹⁹²) and iodine (I¹²⁵).While the preventative and treatment properties of the foregoingbiologically or pharmacologically active substances are well-known tothose of ordinary skill in the art, the biologically orpharmacologically active substances are provided by way of example andare not meant to be limiting. Other biologically or pharmacologicallyactive substances are equally applicable for use with the disclosedmethods and compositions.

Further, a carrier may be used with the biologically orpharmacologically active substance. Examples of suitable carriersinclude, but are not limited to, ethanol, acetone, tetrahydrofuran,dymethylsulfoxide, a combination thereof, or other suitable carriersknown to those skilled in the art. Still further, a surfactant may beformulated with the biologically or pharmacologically active substanceand the solvent to aid elution of the biologically or pharmacologicallyactive substance.

Stents 100, 300, 500 may be used conventionally in blood vessels of thebody to support such a vessel after an angioplasty procedure. It isknown that certain biologically or pharmacologically active substanceseluted from stents may prevent restenosis or other complicationsassociated with angioplasty or stents. Stents 100, 300, 500 mayalternatively be used in other organs or tissues of the body fordelivery of biologically or pharmacologically active substance to treattumors, inflammation, nervous conditions, or other conditions that wouldbe apparent to those skilled in the art.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofillustration and example only, and not limitation. It will be apparentto persons skilled in the relevant art that various changes in form anddetail can be made therein without departing from the spirit and scopeof the invention. Thus, the breadth and scope of the present inventionshould not be limited by any of the above-described exemplaryembodiments, but should be defined only in accordance with the appendedclaims and their equivalents. It will also be understood that eachfeature of each embodiment discussed herein, and of each reference citedherein, can be used in combination with the features of any otherembodiment. Furthermore, there is no intention to be bound by anyexpressed or implied theory presented in the preceding technical field,background, brief summary or the detailed description. All patents andpublications discussed herein are incorporated by reference herein intheir entirety.

What is claimed is:
 1. A stent comprising: a hollow wire formed into astent pattern, the wire having a wire outer surface and a wire innersurface, the wire inner surface defines a wire lumen, wherein prior toimplantation in a body lumen the wire includes, a radiopaque memberlining at least a portion of the wire inner surface, the radiopaquemember having a radiopaque member inner surface and a radiopaque memberouter surface contacting the wire inner surface, a radiopaque memberlumen defined by the radiopaque member inner surface and extendinglongitudinally within the radiopaque member at the portions of the wireinner surface lined by the radiopaque member and defined by the wireinner surface at any portions of the wire inner surface not lined by theradiopaque member, a biologically or pharmacologically active substancedisposed in the radiopaque member lumen, and at least one openingdisposed through the wire outer and inner surfaces to the wire lumen orthrough the wire outer and inner surfaces and the radiopaque member tothe radiopaque member lumen.
 2. The stent of claim 1, wherein theradiopaque member extends along the entire length of the wire innersurface.
 3. The stent of claim 1, wherein the stent pattern comprises awaveform of struts connected by crowns helically wrapped into a tube. 4.The stent of claim 3, wherein the radiopaque member lines the wire innersurface only in the crowns of the waveform.
 5. The stent of claim 3,wherein the radiopaque member lines the wire inner surface in the crownsand portions of the struts of the waveform.
 6. The stent of claim 1,wherein the wire is formed from a material selected from the groupconsisting of stainless steel, nickel-titanium alloys, andcobalt-chromium alloys.
 7. The stent of claim 6, wherein the wire isformed from a cobalt-chromium alloy.
 8. The stent of claim 1, whereinthe radiopaque member is formed from a material selected from the groupconsisting of platinum-iridium alloys, tantalum, and tantalum-tungstenalloys.
 9. The stent of claim 8, wherein the radiopaque member is formedfrom tantalum.
 10. The stent of claim 1, wherein the biologically orpharmacologically active substance is selected from the group consistingof antineoplastic, antimitotic, antiinflammatory, antiplatelet,anticoagulant, anti fibrin, antithrombin, antiproliferative, antibiotic,antioxidant, and antiallergic substances as well as combinationsthereof.
 11. A method of forming a stent comprising the steps of:shaping a composite hollow wire into a stent pattern, wherein the wirehaving a wire outer surface and a wire inner surface, the wire innersurface defines a wire lumen, a radiopaque intermediate member having aradiopaque member inner surface and a radiopaque member outer surfacecontacting the wire inner surface, and a core member, wherein theradiopaque intermediate member is disposed between the wire innersurface and the core member; processing the composite wire such that thecore member is removed without adversely affecting the wire and theradiopaque member, thereby leaving the wire and the radiopaque member,the radiopaque member lining at least a portion of the wire innersurface, and a radiopaque member lumen defined by a space formerlyoccupied by the core member such that the radiopaque member lumen isdefined by the radiopaque member inner surface and extendinglongitudinally within the radiopaque member at the portions of the wireinner surface lined by the radiopaque member and is defined by the wireinner surface at any portions of the wire inner surface not lined by theradiopaque member; filling at least a portion of the radiopaque memberlumen with a biologically or pharmacologically active substance; andproviding openings through at least the wire outer and inner surface tothe wire lumen or through the wire outer and inner surfaces and theradiopaque member to the radiopaque member lumen, such that prior toimplantation in a body lumen the openings extend from the wire outersurface to the wire lumen or the radiopaque member lumen, respectively.12. The method of claim 11, wherein the step of processing the compositewire such that the core member is removed also does not adversely affectthe radiopaque intermediate member, thereby leaving the radiopaquemember lining the wire inner surface, and the radiopaque member lumendefined by the radiopaque intermediate member inner surface along theentire length of the wire inner surface.
 13. The method of claim 12,wherein the wire comprises a cobalt-chromium alloy, the radiopaqueintermediate member comprises a platinum-iridium alloy, the core memberis selected from the group consisting of tantalum, tungsten, molybdenum,niobium, rhenium, carbon, germanium, silicon, and tantalum-tungstenalloys, and the step of removing the core member comprises exposing thecore member to xenon-difluoride.
 14. The method of claim 12, wherein thewire comprises a cobalt-chromium alloy, the radiopaque intermediatemember is selected from the group consisting of tantalum andtantalum-tungsten alloys, the core member comprises copper or silver,and the step of removing the core member comprises exposing the coremember to nitric acid.
 15. The method of claim 12, wherein the wirecomprises a cobalt-chromium alloy, the radiopaque intermediate member isselected from the group consisting of platinum-iridium alloys, tantalum,and tantalum-tungsten alloys, the core member is selected from the groupconsisting of zinc and magnesium, and the step of removing the coremember comprises exposing the core member to water or salt water or heatto melt or sublimate the core member.
 16. The method of claim 11,wherein the step of processing the composite wire such that the coremember is removed also comprises removing portions of the radiopaqueintermediate member such that portions of the wire inner surface are notlined with the radiopaque intermediate member.
 17. The method of claim16, wherein the step of shaping the composite hollow wire into a stentform includes shaping the wire into a waveform including strutsconnected by crowns, and wherein after the step of processing the wireto remove the core member and portions of the radiopaque intermediatemember, the radiopaque intermediate member lines the wire inner surfaceonly in the crowns of the waveform.
 18. The method of claim 16, whereinthe wire comprises a cobalt-nickel-chromium-molybdenum alloy, theradiopaque intermediate member comprises tantalum, the core member isselected from the group consisting of rhenium, molybdenum, tungsten, andalloys thereof, and the step of removing the core member and portions ofthe radiopaque intermediate member comprises exposing the core member toxenon-difluoride such that the core member is etched at a faster ratethan the radiopaque intermediate member.
 19. The method of claim 11,wherein the biologically or pharmacologically active substance isselected from the group consisting of antineoplastic, antimitotic,antiinflammatory, antiplatelet, anticoagulant, anti fibrin,antithrombin, antiproliferative, antibiotic, antioxidant, andantiallergic substances as well as combinations thereof.
 20. The methodof claim 11, wherein the step of providing openings through the at leastone of the wire outer and inner surfaces and the radiopaque membercomprises laser drilling openings through the wire outer and innersurfaces and/or the radiopaque member.
 21. The method of claim 11,wherein the step of providing openings through the at least one of thewire outer and inner surfaces and the radiopaque member occurs beforethe step of processing the wire to remove the core member.
 22. Themethod of claim 11, further comprising the step of removing portions ofthe intermediate member in a separate step from the step of removing thecore member.
 23. The method of claim 22, wherein the step of removingthe core member is a dry etch process and the step of removing portionsof the radiopaque intermediate member is a selective wet etch process.